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Page 2 of 20 Vidoni et al. J Cancer Metastasis Treat 2021;7:4 I http://dx.doi.org/10.20517/2394-4722.2020.95

INTRODUCTION
One of the hallmarks of cancer cells is represented by the enhanced signaling that lead to uncontrolled
cellular growth and proliferation. To support its neoplastic growth and its sustenance under harsh and
stressful conditions, cancer cells reprogram their metabolism alongside with the dynamic crosstalk with
[1-3]
stromal cells in the tumor microenvironment .
Cellular homeostasis largely relies on autophagy, a lysosome-mediated catabolic process that accomplishes
the macromolecular turnover. Altered regulation of this process may lead to the accumulation of damaged
or redundant organelles, unfolded proteins, reactive oxygen species, and oncogenic molecules that favor
[4]
carcinogenesis . Thus, not surprisingly, autophagy is dysregulated in several cancers, among which include
cancers affecting women [5-10] .

Tumorigenesis is linked to genome instability, as well as to epigenetic and metabolic alterations. While
normal cells show a very low rate of mutations, in malignant cells disruption of the DNA repair system
compromises the surveillance machinery, leading to accumulation of spontaneous or carcinogen-induced
[11]
mutations . Particularly, mutations in oncogenes and in tumor suppressor genes, which control cell
behavior and cell fate, allow cancer cells to escape from cell proliferation and cell motility control, avoid
[1]
apoptosis, and survive under harsh metabolic conditions . Besides mutations in the gene sequence that
could affect the activity, the subcellular localization and the function of oncogenic or tumor suppressive
proteins, and the heritable alterations of the mechanisms controlling the expression and translation
(epigenetics) of oncogenes and of tumor suppressor genes also play a role in tumorigenesis. Such
epigenetic mechanisms include hypermethylation/demethylation of the promoter, histone modifications
[12]
(i.e., acetylation/de-acetylation), and post-transcriptional regulation by non-coding RNAs (ncRNAs) .
Metabolic factors (e.g., nutrient and oxygen availability), cellular stressors (e.g., oxidative stress), cell-to-
cell communications, and soluble mediators (e.g., growth factors and cytokines), present in the tumor
microenvironment, greatly affect the dynamic of epigenetic changes in cancer cells, resulting in their
adaptation to a pro-tumorigenic environment [9,13] .

ncRNAs, transcripts without encoding potential, play a pivotal epigenetic role and have been implicated
in tumorigenesis by acting as tumor suppressors or tumor promoters, at transcriptional and post-
transcriptional levels .
[14]
In this article, we review how ncRNAs may impinge on the development and progression of women’s
cancers through the epigenetic control of autophagy.

TUMORS AFFECTING WOMEN AT A GLANCE
We will focus on the most frequent malignancies affecting women, including breast, ovarian, endometrial,
[15]
and cervical cancers .

Breast cancer
Breast cancer is the first diagnosed, in terms of incidence, and the first leading cause of death among
[16]
malignancies affecting women . Based on the presence or absence of predictive factors, such as estrogen
or progesterone hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2), breast
cancer is classified into four primary subtypes: luminal A (HR+/HER2-), luminal B (HR+/HER2+), HER2
positive (HR-/HER2+), and triple-negative (HR-/HER2-). Each subtype differs in incidence, therapeutic
responsiveness, and disease progression [Figure 1]. About 70% of breast cancer patients bear a luminal
A or B subtype, whereas approximately 15% bear a triple-negative subtype lacking both HR and HER2
[17]
expression. HER2 is amplified in around 20% of breast cancers, and it is associated with poor prognosis .