Bowdoin Science Journal

Gisela Contreras '27

From Milk to Malignancy – Breast Cancer and its Metabolic Implications 

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The annual rise of cancer cases has created a high demand for new innovative treatments and has made cancer a prominent topic in the scientific community. According to the American Cancer Society (ACS), approximately 20 million new cancer cases were diagnosed worldwide in 2022, leading to 9.7 million deaths [1]. It is expected that by 2050, cancer cases will reach 35 million, largely due to population growth [1]. While significant advancements have been made in cancer research, the complexity of different cancer types presents challenges. 

One of the most prevalent forms is breast cancer, which, in 2022, was the second most common cancer in the U.S., with 2.3 million new cases, predominantly affecting women [2]. Unlike many cancers, breast cancer is not a single disease but a collection of subtypes characterized by distinct clinical, morphological, and molecular features. This heterogeneity makes it challenging to study and treat effectively. A recent study published in Nature Metabolism explores the metabolic differences between normal mammary cells and breast cancer cells [4]. Understanding these metabolic processes could pave the way for new, targeted therapies. Researchers have identified specific metabolic vulnerabilities in mammary epithelial cells, which line the breast tissue.

 

Figure 1. Non-tumorigenic Mammary Gland Components. A diagram of a non-tumorigenic mammary gland showing a cluster of alveoli containing luminal and basal cells. Luminal cells line the milk ducts and alveoli and are responsible for milk secretion during lactation. Basal cells are believed to play a role in transporting milk to the nipple during lactation. Source: Created in BioRender, [4], [10], [11].

In the normal mammary gland, various types of cells carry out specific functions, one of which is the progenitor cells. These progenitor cells generate distinct alveolar structures that continuously form in the adult breast, and their activity is crucial for maintaining normal mammary homeostasis [5]. Progenitor cells are located in the luminal compartment [6], which is also home to the luminal cells. The luminal cells play a key role in lactation by lining the milk ducts and alveoli, where they secrete milk (Figure 1)[7]. In contrast, basal cells are located around the luminal cells and are believed to function during lactation by helping to transport milk to the nipple (Figure 1)[7]. Although these mammalian epithelial cells (luminal and basal cells) are important to the function of normal mammary glands, these also serve as a tumour cell of origin [4].

In their study, Mahendralingam et al. used mass spectrometry to analyze the metabolic profiles of normal human mammary cells [8]. They discovered that luminal progenitor cells primarily rely on oxidative phosphorylation for energy, whereas basal cells depend more on glycolysis [4]. This distinction is crucial because oxidative phosphorylation is an efficient, oxygen-dependent process that generates substantial energy, while glycolysis, though faster, is less efficient and does not require oxygen — a pathway often favored by cancer cells to support rapid growth [9]. Targeting these distinct energy pathways could lead to more effective treatments for different breast cancer subtypes.

However, a new discovery was that breast cancer cells appear to adopt the metabolic programs of their cells of origin [4,9]. This complicates treatment since the cancer cells may still be vulnerable to metabolic pathways that are important for normal cell function. As a result, treatments designed to target specific metabolic pathways might not work as expected, since the cancer cells might behave similarly to the healthy cells from which they originated. 

The results from Mahendralingam et al. can form a basis for future metabolic studies that may lead to specific anti-tumoral drug therapies designed to treat specific breast cancer subtypes. This type of research lays a foundation for targeted approaches but further studies are needed to assess how findings, such as this one, can translate into clinical practice. As breast cancer continues to rise, understanding the complexity is more important than ever. 

 

Work Cited: 

  1. Global Cancer Facts & Figures. (n.d.). Retrieved October 27, 2024, from https://www.cancer.org/research/cancer-facts-statistics/global-cancer-facts-and-figures.html
  2. Global cancer burden growing, amidst mounting need for services. (n.d.). Retrieved October 27, 2024, from https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing–amidst-mounting-need-for-services
  3. Sánchez López de Nava, A., & Raja, A. (2024). Physiology, Metabolism. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK546690/
  4. Alfonso-Pérez, T., Baonza, G., & Martin-Belmonte, F. (2021). Breast cancer has a new metabolic Achilles’ heel. Nature Metabolism, 3(5), 590–592. https://doi.org/10.1038/s42255-021-00394-8
  5. Tharmapalan, P., Mahendralingam, M., Berman, H. K., & Khokha, R. (2019). Mammary stem cells and progenitors: Targeting the roots of breast cancer for prevention. The EMBO Journal, 38(14), e100852. https://doi.org/10.15252/embj.2018100852
  6. Tornillo, G., & Smalley, M. J. (2015). ERrrr…Where are the Progenitors? Hormone Receptors and Mammary Cell Heterogeneity. Journal of Mammary Gland Biology and Neoplasia, 20(1–2), 63–73. https://doi.org/10.1007/s10911-015-9336-1
  7. New Paradigm for Mammary Glands. (n.d.). Massachusetts General Hospital. Retrieved December 8, 2024, from https://www.massgeneral.org/cancer-center/clinician-resources/advances/new-paradigm-for-mammary-glands
  8. Mahendralingam, M. J., Kim, H., McCloskey, C. W., Aliar, K., Casey, A. E., Tharmapalan, P., Pellacani, D., Ignatchenko, V., Garcia-Valero, M., Palomero, L., Sinha, A., Cruickshank, J., Shetty, R., Vellanki, R. N., Koritzinsky, M., Stambolic, V., Alam, M., Schimmer, A. D., Berman, H. K., … Khokha, R. (2021). Mammary epithelial cells have lineage-rooted metabolic identities. Nature Metabolism, 3(5), 665–681. https://doi.org/10.1038/s42255-021-00388-6
  9. ZHENG, J. (2012). Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncology Letters, 4(6), 1151–1157. https://doi.org/10.3892/ol.2012.928
  10. Fig. 3 Stem cell in glandular and stratified epithelia. A A schematic… (n.d.). ResearchGate. Retrieved December 7, 2024, from https://www.researchgate.net/figure/Stem-cell-in-glandular-and-stratified-epithelia-A-A-schematic-model-depicting-the_fig3_374804603
  11. Model of normal mammary gland structure. This tissue is composed of… (n.d.). ResearchGate. Retrieved December 8, 2024, from https://www.researchgate.net/figure/Model-of-normal-mammary-gland-structure-This-tissue-is-composed-of-ducts-which-are_fig1_357239665

Infertility: The Unknown

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The term “infertility” often has a negative social stigma that is damaging to many couples hoping to start a family. The reputation that precedes infertility is often blamed on women, which can cause a lot of pressure and lead to misinformation about the topic. While infertility affects women at different stages in life, aging is an important contributing factor to the decline in women’s fertility. Infertility can be defined in many terms, but the CDC defines infertility as a woman aged 35 years or younger not being able to get pregnant after one year or longer of unprotected sex. Furthermore, a woman aged 35 years or older, can be considered infertile after 6 months of unprotected sex[1]. Many couples experience infertility correlated to genetics and reproductive health, but this problem also involves other complex issues like social, economic, and cultural implications[2]. Fertility is an important societal issue, and the World Health Organization (WHO) states that nearly 50-80 million people face some sort of infertility. Ever since the first IVF baby was born in 1978, the demand for fertility treatments has increased and driven many patients to look at the scientific world for new developments to conceive children or genetically test their embryos[3]. Science has paved a pathway with new techniques to treat infertility, like IVF, pre-implantation genetic testing or screening (PGT/S) of embryos, and other modern instruments that offer more opportunities to improve infertility care[4]. While all of these technological advancements help infertility patients, many questions remain about what the leading causes of infertility are. 

In 2009, Roupa et al. conducted a study in Greece to investigate which were the most prevalent causes of infertility in women of reproductive age[2]. In the study, the women of reproductive age ranged from 20 to over 50 years of age. This study consists of 110 infertile women who sought medical assistance from the Center for Assisted Reproduction for a period of two months. From this center, these women were randomly sampled and agreed to participate in the study. To collect data, researchers constructed a specific questionnaire that included demographic data and questions concerning their infertility.

The results from this study showcase the broad causes of infertility — specifically the top three leading causes. The first leading cause of infertility problems, 27.4%, was issues with the fallopian tubes, which may reference the blockage or scarring of the fallopian tubes[5]. This can result from malformation, endometriosis adhesions, inflammatory diseases, infections, and sexually transmitted diseases[6]. The fallopian tubes serve as channels for the transportation of eggs to the uterus[6] but if the fallopian tubes are blocked, the eggs are not able to move from the ovaries to the uterus which makes the sperm unable to fertilize the egg[5]. The second leading cause of infertility problems, 24.5%, is due to unknown causes. This is almost a quarter of the study’s results, which leads to the conclusion that further and more in-depth research needs to be done to investigate the causes of failed conception like further individualized treatment[7]. The third leading cause of infertility problems, 20.0%, was due to disorders of menstruation. Disorders of menstruation is a broad term to classify physical or emotional problems that affect the normal menstrual cycle, unusually heavy or light bleeding, and missed periods[8]. Some examples of menstrual disorders are abnormal uterine bleeding, the absence of menstruation, and Premenstrual Syndrome (PMS), to name a few[8]. Although there were other infertility causes like problems in the uterus (9.1%), sexual disorders (2.6%), and ovarian deficiency (3.6%), the three major leading causes that affected the majority of the study were fallopian tube problems, unknown causes, and disorders of menstruation.

There are disorders, syndromes, and diseases that give women insight into the possible causes of infertility they experience, but still, nearly a quarter of the study participants weren’t able to identify their issue. Although more research has started to be done, only 151 articles related to the study of infertility have been published from 2001 to 2021[9], illustrating that infertility needs to be focused on more within modern research. Age is an important factor for fertility because the health of eggs is reflected by both the quantity and quality of the eggs[10], but age is just one cause. There are more causes of infertility that women suffer from that go beyond being at a “reproductive age” that are undiscovered. The reality is that the infertility research field is understudied due to the lack of funding compared to other fields, like cancer. From 2016 to 2019, the National Institutes of Health (NIH) awarded less than 100 projects totaling around $83 million for female-based research on infertility[11], while awarding more than 16,000 grants for cancer research and over $14 billion in funding.[12]. The lack of awards, less than 100 projects awarded in three years, is a shocking statement that highlights the lack of funding the field has. Many causes of infertility are understudied because of the lack of funding, thus the rate of development has been hindered. The truth is that infertility is increasing every year, ​​and fertility rates in the United States have gradually declined from 1990 to 2019. In 1990 there were about 70.77 births each year for every 1,000 women aged 15-44, and by 2019 there were 58.21 births per 1,000 women in that age group[13]. If fertility rates continue to decrease year by year, and no stable funding is available for the sexual and reproductive healthcare system, a true epidemic will occur. The government needs to start taking this problem seriously and allocate stable funding towards researching the numerous causes of infertility. Not only would this benefit many women who have no diagnosis of infertility but it would help the fertility rates around the nation go up.

 

Works Cited –

  1. CDC. (2023, April 26). What is Infertility? Centers for Disease Control and Prevention. https://www.cdc.gov/reproductivehealth/features/what-is-infertility/index.html
  2. Roupa, Z., Polikandrioti, M., Sotiropoulou, P., Faros, E., Koulouri, A., Wozniak, G., & Gourni, M. (2009). Causes of infertility in women at reproductive age. Health Science Journal, 3, 80–87.
  3. Eskew, A. M., & Jungheim, E. S. (2017). A History of Developments to Improve in vitro Fertilization. Missouri Medicine, 114(3), 156–159.
  4. de Santiago, I., & Polanski, L. (2022). Data-Driven Medicine in the Diagnosis and Treatment of Infertility. Journal of Clinical Medicine, 11(21), 6426. https://doi.org/10.3390/jcm11216426
  5. Eunice Kennedy Shriver National Institute of Child Health and Human Development—NICHD. (n.d.). Retrieved April 18, 2024, from https://www.nichd.nih.gov/health/topics/factsheets/infertility
  6. Han, J., & Sadiq, N. M. (2024). Anatomy, Abdomen and Pelvis: Fallopian Tube. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK547660/
  7. Sadeghi, M. R. (2015). Unexplained Infertility, the Controversial Matter in Management of Infertile Couples. Journal of Reproduction & Infertility, 16(1), 1–2.
  8. Igbokwe and, U. C., & John-Akinola, Y. O. (2021). KNOWLEDGE OF MENSTRUAL DISORDERS AND HEALTH SEEKING BEHAVIOUR AMONG FEMALE UNDERGRADUATE STUDENTS OF UNIVERSITY OF IBADAN, NIGERIA. Annals of Ibadan Postgraduate Medicine, 19(1), 40–48.
  9. Zhu, H., Shi, L., Wang, R., Cui, L., Wang, J., Tang, M., Qian, H., Wei, M., Wang, L., Zhou, H., & Xu, W. (2022). Global Research Trends on Infertility and Psychology From the Past Two Decades: A Bibliometric and Visualized Study. Frontiers in Endocrinology, 13, 889845. https://doi.org/10.3389/fendo.2022.889845
  10. George, K., & Kamath, M. S. (2010). Fertility and age. Journal of Human Reproductive Sciences, 3(3), 121–123. https://doi.org/10.4103/0974-1208.74152
  11. Gumerova, E., Jonge, C. J. D., & Barratt, C. L. R. (2021). Research Funding for Male Reproductive Health and Infertility in the UK and USA [2016 – 2019] (p. 2021.08.23.456936). bioRxiv. https://doi.org/10.1101/2021.08.23.456936
  12. McIntosh, S. A., Alam, F., Adams, L., Boon, I. S., Callaghan, J., Conti, I., Copson, E., Carson, V., Davidson, M., Fitzgerald, H., Gautam, A., Jones, C. M., Kargbo, S., Lakshmipathy, G., Maguire, H., McFerran, K., Mirandari, A., Moore, N., Moore, R., … Head, M. G. (2023). Global funding for cancer research between 2016 and 2020: A content analysis of public and philanthropic investments. The Lancet Oncology, 24(6), 636–645. https://doi.org/10.1016/S1470-2045(23)00182-1
  13. Bureau, U. C. (n.d.). Stable Fertility Rates 1990-2019 Mask Distinct Variations by Age. Census.Gov. Retrieved May 2, 2024, from https://www.census.gov/library/stories/2022/04/fertility-rates-declined-for-younger-women-increased-for-older-women.html